Hy. Cheng et al., CARVEDILOL-LIPOSOME INTERACTION - EVIDENCE FOR STRONG ASSOCIATION WITH THE HYDROPHOBIC REGION OF THE LIPID BILAYERS, Biochimica et biophysica acta. Biomembranes, 1284(1), 1996, pp. 20-28
Carvedilol (Kredex, Coreg) is a multiple action antihypertensive drug
that has been shown to protect cell membranes from lipid peroxidative
damages. In this study the physical and structural effects of carvedil
ol an lipid bilayers are investigated by fluorescence techniques, diff
erential scanning calorimetry and other physical methods. Carvedilol b
inds to liposomal membranes (9:1 DMPC:DMPG) strongly with an apparent
binding constant on the order of 10(4) M(-1) in PBS (pH 7.4). The char
acteristic changes in its intrinsic fluorescence properties when bound
to liposomes suggest that this compound is situated in a non-polar en
vironment The Stern-Volmer and bimolecular quenching constants, determ
ined using nitrate as the fluorescence quencher, for the free and boun
d carvedilol indicate that the carbazole moiety is at a depth or >11 A
ngstrom in the lipid bilayer. Fluorescence anisotropy measurements sho
w that, unlike the membrane probes DPII and TMA-DPA, carvedilol is rel
atively mobile, and does not have a rigidly-defined molecular orientat
ion in the bilayers. Differential scanning calorimetry results indicat
e that carvedilol is an effective membrane 'fluidizer' as it dose-depe
ndently lowers the gel to liquid crystalline transition temperature an
d broadens the endothermic transition. Comparative studies of interact
ions of carbazole. 4 OH carbazole and carvedilol with the model liposo
mal membranes reveal a possible role of membrane-partitioning in their
antioxidant efficacy. These findings are discussed in perspective wit
h the membrane biophysical properties of different classes of therapeu
tic significant lipid antioxidants in mind.